Exploring the role of the immune system in maladaptive pain sensitisation

在生理环境中，疼痛敏感化是一种保护机制，其功能是防止进一步的组织损伤并促进愈合。在细胞水平上，这是以伤害性感受器的反应性增加为特征的，这是由于神经元放电阈值的增加和/或反应规模的增加。然而，在病理环境中，不适当的疼痛敏感化是许多衰弱疾病的关键特征，包括类风湿性关节炎(RA)。作为慢性炎症性疾病，RA的疼痛敏感化伴随着血源性免疫细胞向关节滑膜的募集和渗透，这些细胞包括淋巴细胞、巨噬细胞和中性粒细胞。在滑膜，这些免疫细胞通过释放IL-1B、IL-6和肿瘤坏死因子等促炎介质来促进炎症。最近，有证据表明，分泌的促炎蛋白与存在于伤害性感受器上的受体之间存在相互作用，这可能在促进疼痛敏感性方面发挥作用。然而，这些细胞间的相互作用和潜在的机制尚未完全了解。在这里，这项计划采用了一系列的研究方法，从原代细胞培养到体内模型，从聚合酶链式反应到行为学实验，来描绘血液来源的免疫细胞在外周伤害性感受器敏化中的作用。这可能最终对未来的治疗有意义。

In a physiological setting, pain sensitisation is a protective mechanism that functions to prevent further tissue damageand promote healing. At a cellular level, this is characterised by an increased responsiveness of nociceptors, owed to adecrease in threshold for neuronal firing and/or increase in the scale of the response. However, in a pathological setting,inappropriate pain sensitisation is a key feature of many debilitating disorders, including rheumatoid arthritis (RA). As achronic inflammatory disease, the pain sensitisation in RA is accompanied by the recruitment and infiltration of bloodderived immune cells to the synovial membrane of joints, these include lymphocytes, macrophages and neutrophils. Atthe synovium these immune cells promote inflammation by releasing proinflammatory mediators such as interleukin (IL)-1B, IL-6 and tumour necrosis factor a. Recently, evidence has emerged to suggest interactions between the secretedproinflammatory proteins and receptors present on nociceptors, which may play a role in facilitating pain sensitisation.However, these intercellular interactions and underlying mechanisms are yet to be fully understood. Here, this projectaims to employ a combination of research methods, ranging from primary cell cultures to in vivo models and PCR tobehavioural experiments, to delineate the role of blood derived immune cells in the sensitisation of peripheralnociceptors.This may ultimately have implications for future therapeutics.